Ola Weiland

Randomised, double-blind, placebo-controlled trial of interferon α-2b with and without ribavirin for chronic hepatitis C

Summary Background Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon α-2b and ribavirin than with interferon α-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon α-2b and ribavirin compared with interferon α-2b alone. Methods In this double-blind trial 100 patients were randomly assigned to treatment with interferon α-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat. Findings 18 (36%) of the 50 patients in the interferon α-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon α-2b and placebo group (p=0·047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon α-2b and ribavirin group than the interferon α-2b and placebo group (42 vs 20%, p=0·03), respectively. More patients with baseline HCV-RNA concentrations greater than 3×10 6 genome equivalents (Eq) per ml had a sustained response with interferon α-2b and ribavirin than with interferon α-2b and placebo (12/29 vs 1/26, p=0·009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3×10 6 Eq per ml (6/21 vs 8/24, p=0·67), respectively. Interpretation More patients with chronic hepatitis C have a sustained virological response with interferon α-2b and ribavirin than with only interferon α-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon α-2b and ribavirin.

Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study

BACKGROUND/AIMS Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited.

Ribavirin treatment for chronic hepatitis C

We evaluated oral ribavirin as therapy for chronic hepatitis C infection in a pilot study including 10 patients. Patients (7 men, 3 women; mean age 40 years, range 23-54) all had biopsy-proven chronic non-A, non-B hepatitis and were repeatedly positive for antibodies to hepatitis C virus. Treatment was with oral ribavirin 1000-1200 mg per day in two divided doses for 12 weeks. The median serum alanine aminotransferase concentration for all patients at enrollment was 3.15 mu kat/l (range 1.22-7.79) and decreased significantly (p less than 0.005) to 1.25 mu kat/l (0.78-2.04) after 12 weeks of treatment. Within 6 weeks of the end of treatment the median serum alanine aminotransferase concentration was not significantly different from that before treatment. Side-effects were mild and fully reversible after cessation of therapy. We conclude that ribavirin is the first drug to offer a potentially effective oral treatment for chronic hepatitis C. It should be further evaluated in controlled trials, possibly in combination with interferon alpha.

The antiviral compound ribavirin modulates the T helper (Th)1/Th2 subset balance in hepatitis B and C virus-specific immune responses

Ribavirin is effective in combination therapies against chronic hepatitis C virus (HCV) infection, although its direct antiviral properties are unclear. We therefore studied the immune-modulatory effects of ribavirin on hepatitis B virus (HBV)- and HCV-specific immune responses. During a 24 week placebo-controlled ribavirin trial in ten patients with chronic HCV infection, HCV antibodies and alanine aminotransferase (ALT) levels decreased transiently whereas the serum levels of HCV RNA remained stable. Effects of ribavirin on human and murine phytohaemagglutinin (PHA)-activated T cells included inhibition of in vitro proliferation and modulation of IL-2, IL-4, IFN-gamma and TNF-alpha levels. HBcAg- and HBeAg-specific IL-2 and IFN-gamma levels were > or = 25-fold higher in mice immunized with HBV core- or e-antigens (HBcAg, HBeAg) while receiving ribavirin compared to untreated mice, but IL-4 and IL-6 remained constant. Concordantly, a slight shift was observed in the IgG subclass distribution of the humoral responses of ribavirin-treated mice to HBeAg and HCV NS3 protein. Ribavirin treatment of HBeAg-transgenic (HBeAg-Tg) mice induced a dose-dependent down-regulation of T helper (Th)2-mediated antibody production to HBeAg. In ribavirin-treated HBeAg-Tg mice anti-HBe IgG1 (positively regulated by Th2 cytokines) decreased simultaneously as both anti-HBe IgG2a (positively regulated by Th1 cytokines) levels and in vitro T-cell IFN-gamma production increased, indicating a change in the Th1/Th2 balance. Thus, the present data suggest that ribavirin is not strictly an antiviral compound, but rather it alters the T-cell balance in the immune system.

Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy

Background: The key end point for treatment efficacy in chronic hepatitis C is absence of detectable virus at six months after treatment. However, the incidence of clinical events during long term follow up of patients with sustained virological response is still poorly documented and may differ between the Eastern and Western world. Aims: To assess clinical end points during long term follow up of European patients with a sustained virological response to interferon monotherapy. Methods: Meta-analysis of individual patient data from eight European protocolled follow up studies of interferon treatment for chronic hepatitis C. Results: A total of 286 sustained virological responders and 50 biochemical responders (detectable virus but normal alanine aminotransferase levels) were followed up for 59 months. Fifteen sustained virological responders (5.2%) had cirrhosis before treatment and 112 (39%) had genotype 1. The late virological relapse rate after five years of follow up was 4.7% (95% confidence interval (CI) 2.0–7.4) among sustained virological responders; all late relapses occurred within four years after treatment. Among sustained virological responders, the rate of decompensation after five years of follow up was 1.0% (95% CI 0.0–2.3) and none developed hepatocellular carcinoma (HCC). Survival was comparable with the general population, matched for age and sex, the standard mortality ratio being 1.4 (95% CI 0.3–2.5). Clinical outcome of patients with cirrhosis was similar to other sustained virological responders. For biochemical responders, the rates of development of decompensation and HCC during long term follow up were 9.1% (95% CI 0.5–17.7) and 7.1% (95% CI 0–15.0), respectively. Conclusions: Five year survival of European sustained virological responders was similar to the overall population, matched for age and sex. No HCCs were detected during long term follow up.

Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon

BACKGROUND/AIMS This study aimed to determine the long-term outcome of hepatitis C virus (HCV)-infected patients who respond to interferon treatment with clearance of serum HCV RNA. METHODS We performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994. RESULTS At biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5-8.8 years (mean +/- SD, 5.4+/-1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1-8.7 years (mean +/- SD, 5.0+/-1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients. CONCLUSION In this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.

Unexpected high prevalence of IgG-antibodies to hepatitis E virus in Swedish pig farmers and controls

Hepatitis E virus (HEV) infections are responsible for large waterborne outbreaks in developing countries. Sporadic cases in the developed world are mainly imported via immigrants and travellers from endemic areas. HEV has been suggested to be a zoonotic infection where pigs may be an important reservoir for the disease and specific swine strains of HEV have been identified which can infect also humans. The aim of this study was to analyse if Swedish pig farmers are more exposed to HEV than persons with other occupations. A total of 115 male pig farmers aged 40–60 y and 108 age- and geographically- matched control subjects were tested for IgG anti-HEV antibodies. No statistical difference in anti-HEV prevalence was noted between pig farmers (13.0%) and control subjects (9.3%). The prevalence of anti-HEV antibodies in the pig farmers and controls was higher than that previously reported among other populations in Europe (<1 – 9%). Further studies are needed to elucidate the routes for infection of indigenous HEV and if sub-clinical infections with pig associated HEV strains occur in Sweden.

Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: A nationwide study

Objective. Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH. Material and methods. Analyses were performed in 473 patients identified as having probable or definite AIH. Results. The incidence of AIH was 0.85/100,000 (95% CI 0.69–1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8–13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected “en passant” to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%). Conclusions. The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. Design In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. Trial registration number NCT01125189.

Expansion of Functionally Skewed CD56-Negative NK Cells in Chronic Hepatitis C Virus Infection: Correlation with Outcome of Pegylated IFN-α and Ribavirin Treatment

NK cells are important innate immune effector cells, normally characterized as CD56+CD3− lymphocytes. In this study, we report that CD56−CD16+ NK cells expand in many patients with chronic hepatitis C virus infection. These CD56− NK cells were functionally impaired with respect to cytokine production upon target cell recognition, in comparison to CD56dim and CD56bright NK cell subsets. In particular, CD56− NK cells were strikingly defective in their polyfunctional response as measured by the coexpression of MIP-1β, IFN-γ, TNF-α, and CD107a degranulation. The ability of these cells to mediate three or four of these functions was poor; expression of MIP-1β alone dominated their response. CD56− NK cells retained expression of receptors such as the natural cytotoxicity receptors and NKG2D, whereas the expression of CD57 and perforin was lower when compared with CD56dim NK cells. Interestingly, pretreatment levels of CD56− NK cells correlated with the outcome of pegylated IFN-α and ribavirin treatment. In patients with CD56− NK cells in the range of healthy subjects, 80% reached a sustained virological response to treatment, whereas only 25% of patients with levels clearly above those in healthy subjects experienced a sustained virological response. Thus, chronic hepatitis C virus infection is associated with an expansion of CD56− NK cells functionally skewed toward MIP-1β production only. Furthermore, high levels of these cells reveal a disturbance in innate cellular immunity that is associated with an impaired ability to respond to antiviral treatment with IFN-α and ribavirin.